With millions of people world-wide dying from cancer each year, there is an ever present need for improved therapeutic options. A host of chemotherapeutic agents have been developed in an effort to combat the various forms of the disease. Examples of classes of chemotherapeutic agents include alkylating agents, antibiotics, antimetabolites, differentiating agents, mitotic inhibitors, steroids, topoisomerase inhibitors, and tyrosine kinase inhibitors (TKIs). TKIs block the phosphorylation of proteins to inhibit activation of signal transduction pathways that support tumor development and progression. Receptor tyrosine kinase inhibitors (RTKIs) are TKIs that specifically target the activity of receptor tyrosine kinase (RTK) proteins such as epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR). However, the effectiveness of RTKIs and other chemotherapy drugs is often hindered by the intrinsic or acquired resistance of cancer cells to anticancer agents.
One contributing factor to the resistance of tumors to chemotherapy is the presence of cancer stem cells (CSCs) within cancer cell populations. CSCs are undifferentiated cells that constitute a small subset (typically less than 10%) of cancer cells. CSCs are so named because they possess some of the characteristics of embryonic stem cells and can differentiate into a variety of cancer cell types. CSCs are therefore tumorigenic and can lead to cancer relapse and metastasis. Many chemotherapeutic drugs kill differentiated cancer cells, but fail to effectively eliminate CSCs, allowing those cells to proliferate and the cancer to persist, resulting in the overall resistance of the tumor to eradication.
Two RTKIs approved for use in treating cancer are erlotinib (Tarceva®, OSI Pharmaceuticals) and gefitinib (Iressa®, AstraZeneca). Both drugs target and inhibit EGFR. Activation of EGFR following the binding of epidermal growth factor (EGF) or another ligand to the receptor results in the ATP-driven phosphorylation of tyrosine residues located in the intracellular domain of the receptor. The phosphorylated tyrosines then interact with other intracellular proteins and activate signal transduction pathways to promote cell survival and proliferation. Increased activation of EGFR is associated with a variety of cancer types, especially tumors derived from epithelial cells. The increase in receptor activity can result from mutations in the kinase domain of EGFR, amplification of EGFR gene expression, or overexpression of the EGFR protein (Yauch et al., Clinical Cancer Research. 2005; 11(24):8686-98). Erlotinib and gefitinib, as well as other RTKIs, interfere with the ATP-binding domain of RTKs to suppress receptor activation and block downstream signal transduction.
Erlotinib and gefitinib were the first RTKIs approved for use in treating non-small cell lung cancer (NSCLC). Lung cancer is the leading cause of cancer deaths worldwide, and about 85-90% of lung cancer patients have NSCLC (Gottschling et al. Lung Cancer. 2012; 77(1):183-91). The effectiveness of erlotinib and gefitinib in treating NSCLC has been limited, with most patients continuing to exhibit disease progression following initiation of therapy (Witta et al., Cancer Research. 2006; 66(2):944-950). Patients with certain EGFR mutations have been found to respond better to treatment with RTKIs than those with wild-type EGFR. Approximately 70-80% of NSCLC patients with EGFR mutations are sensitive to RTKI therapy, however, virtually all patients eventually acquire resistance (Suda et al. Journal of Thoracic Oncology. 2011; 6(7):1152-61). Additionally, the prevalence of the mutations is relatively rare, occurring in less than 20% of patients (Yauch 2005, supra). Overall, only about 10% of Caucasian NSCLC patients exhibit significant changes in disease progression following therapy with erlotinib or gefitinib (Gottschling 2012, supra), underscoring the need for improved therapeutic methods.
Gliadin is a protein found in wheat and related grains and is one of the main components of gluten. The four main types of gliadin are alpha, beta, gamma, and omega. Gliadin can be digested into a number of active peptides, including some that trigger T-cell immunity or cytotoxicity. Gliadin has been extensively studied for its role in celiac disease, a chronic inflammatory condition related to dietary gluten, but has not been disclosed or suggested for use as an anticancer agent, either alone or in combination with conventional chemotherapeutic agents. In fact, treatment of various cell types, including cancer cells, with gliadin peptides has been demonstrated to activate the EGFR pathway and induce cell proliferation (Barone et al. Gut. 2007; 56(4):480-488), which strongly suggests that gliadin administration is contraindicated for the treatment of cancer.